We are studying cytokine and chemokine responses to influenza A infection in humans, and the effects of new antiviral drugs on the course of influenza infection and the host immune responses elicited by it. We characterized local and circulating levels of IL-2, IFN-alpha, IFN-gamma, IL-4, IL-6, IL-8. IL-10, IL-12, TGF-beta, TNF-alpha, MIP-1 alpha, MIP-1 beta, MCP-1 and RANTES. We documented a reproducible and predictable course of cytokine and chemokine responses with significant elevations in nasal secretions of IFN-alpha, IL-6, IL-8, IL-10, TNF-alpha, INF-alpha and gamma, MCP-1, and MIP-1 alpha and beta. By obtaining specimens on a daily basis through the course of infection and documenting patient upper respiratory, lower respiratory and systemic symptoms as well as body temperature and quantity of virus shed in nasal secretions, we correlated disease severity and virus yield with prompt rises in local and circulating IL-6, TNF-alpha and some chemokines. We documented that potent new inhibitors of influenza A virus replication markedly attenuate the influenzal syndrome and lead to a significantly reduced cytokine responses. We showed that the correlations between illness severity and cytokine and chemokine release holds both for experimental influenza and for community-acquired influenza A virus infections.